Ketogenesis

[1][2] The process supplies energy to certain organs, particularly the brain, heart and skeletal muscle, under specific scenarios including fasting, caloric restriction, sleep,[3] or others.

(In rare metabolic diseases, insufficient gluconeogenesis can cause excessive ketogenesis and hypoglycemia, which may lead to the life-threatening condition known as non-diabetic ketoacidosis.

[citation needed] Recent evidence suggests that glial cells are ketogenic, supplying neurons with locally synthesized ketone bodies to sustain cognitive processes.

[7] Ketogenesis in healthy individuals is ultimately under the control of the master regulatory protein AMPK, which is activated during times of metabolic stress, such as carbohydrate insufficiency.

Its activation in the liver inhibits lipogenesis, promotes fatty acid oxidation, switches off acetyl-CoA carboxylase, turns on malonyl-CoA decarboxylase, and consequently induces ketogenesis.

[8] Ethanol is a potent AMPK inhibitor[9] and therefore can cause significant disruptions in the metabolic state of the liver, including halting of ketogenesis,[6] even in the context of hypoglycemia.

[11] Depletion of glucose and oxaloacetate can be triggered by fasting, vigorous exercise, high-fat diets or other medical conditions, all of which enhance ketone production.

[12] Deaminated amino acids that are ketogenic, such as leucine, also feed TCA cycle, forming acetoacetate & ACoA and thereby produce ketones.

[2] The three ketone bodies, each synthesized from acetyl-CoA molecules, are: β-Hydroxybutyrate and acetoacetate can pass through membranes easily, and are therefore a source of energy for the brain, which cannot directly metabolize fatty acids.

Glucagon activates hormone-sensitive lipase and inhibits acetyl-CoA carboxylase, thereby stimulating ketone body production, and making passage into the mitochondria for β-oxidation easier.

Without insulin to help extract glucose from the blood, tissues the levels of malonyl-CoA are reduced, and it becomes easier for fatty acids to be transported into mitochondria, causing the accumulation of excess acetyl-CoA.